Amides of 6-hydroxy-PGE1 compounds

ABSTRACT

The present invention provides amides of 6-hydroxy-PGE 1  compounds which are useful pharmacological agents. These analogs are useful as prostacyclin-like drugs.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of Ser. No. 812,794, filed July 5, 1977, now issued as U.S. Pat. No. 4,131,738.

The present invention relates to amides of 6-hydroxy-PGE₁ compounds, the preparation and use of which are described in U.S. Ser. No. 812,794, filed July 5, 1977, now issued as U.S. Pat. No. 4,131,738 on Dec. 26, 1978.

The essential material constituting a disclosure of the instant invention is incorporated by reference here from U.S. Pat. No. 4,131,738. 

I claim:
 1. A prostacyclin analog of the formula ##STR1## wherein R₈ is hydrogen, hydroxy, or hydroxymethyl; WHEREIN Z₁ is(1) --(CH₂)_(g) --CH₂ --CH₂ --, (2) --(ch₂)_(g) --CH₂ --CF₂ --, or (3) trans--(CH₂)_(g) --CH═CH--,wherein g is the integer one 2 or 3; Wherein Y₁ is (1) trans--CH═CH--, (2) cis--CH═CH--, (3) --ch₂ ch₂ --, (4) trans--CH═C(Hal)--, or (5) --C.tbd.C--,wherein Hal is chloro or bromo; Wherein M₁ is ##STR2## wherein R₅ is hydrogen or alkyl with one to 4 carbon atoms, inclusive; Wherein L₁ is ##STR3## or a mixture of ##STR4## and ##STR5## wherein R₃ and R₄ are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R₃ and R₄ is fluoro only when the other is hydrogen or fluoro; Wherein L₄ is (a) amino of the formula --NR₂₁ R₂₂, wherein R₂₁ and R₂₂ are hydrogen; alkyl of one to 12 carbon atoms, inclusive; cycloalkyl of 3 to 10 carbon atoms, inclusive; aralkyl of 7 to 12 carbon atoms, inclusive; phenyl; phenyl substituted with one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive; hydroxy; carboxy, alkoxycarbonyl of one to 4 carbon atoms, inclusive; or nitro; carboxyalkyl of one to 4 carbon atoms, inclusive; carbamoylalkyl of one to 4 carbon atoms, inclusive; cyanoalkyl of one to 4 carbon atoms, inclusive; acetylalkyl of one to 4 carbon atoms, inclusive; benzoylalkyl of one to 4 carbon atoms, inclusive; benzoylalkyl substituted by one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive; hydroxy, alkoxy of one to 3 carbon atoms, inclusive; carboxy, alkoxycarbonyl of one to 4 carbon atoms, inclusive; or nitro; pyridyl; pyridyl substituted by one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive; or alkoxy of one to 3 carbon atoms, inclusive; pyridylalkyl of one to 4 carbon atoms, inclusive; pyridylalkyl of one to 4 carbon atoms, inclusive; pyridylalkyl substituted by one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive; hydroxy, alkoxy of one to 3 carbon atoms, inclusive; hydroxyalkyl of one to 4 carbon atoms, inclusive; dihydroxyalkyl of one to 4 carbon atoms, and trihydroxyalkyl of one to 4 carbon atoms; with the further proviso that not more than one of R₂₁ and R₂₂ is other than hydrogen or alkyl; (b) cycloamino selected from the group consisting of ##STR6## wherein R₂₁ and R₂₂ are as defined above; (c) carbonylamino of the formula --NR₂₃ COR₂₁, wherein R₂₃ is hydrogen or alkyl of one to 4 carbon atoms and R₂₁ is as defined above; (d) sulfonylamino of the formula --NR₂₃ SO₂ R₂₁, wherein R₂₁ and R₂₃ are as defined above; or (e) hydrazino of the formula --NR₂₃ R₂₄, wherein R₂₄ is amino of the formula --NR₂₁ R₂₂, as defined above, or cycloamino, as defined above;wherein R₇ is (1) --(CH₂)_(m) --CH₃, ##STR7## wherein m is the integer one to 5, inclusive, h is the integer zero to 3, inclusive; s is the integer zero, one, 2, or 3, and T is chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, or with the proviso that not more than two T's are other than alkyl.
 2. A prostacyclin analog according to claim 1, wherein R₈ is hydroxymethyl.
 3. 11-Deoxy-11α-hydroxymethyl-6-hydroxy-PGE₁, amide, a prostacyclin analog according to claim
 2. 4. A prostacyclin analog according to claim 1, wherein R₈ is hydrogen.
 5. 11-Deoxy-6-hydroxy-PGE₁, amide, a prostacyclin analog according to claim
 4. 6. A prostacyclin analog according to claim 1, wherein R₈ is hydroxy.
 7. A prostacyclin analog according to claim 6, wherein ˜OH is beta.
 8. 6β-Hydroxy-PGE₁, amide, a prostacyclin analog according to claim
 7. 9. A prostacyclin analog according to claim 6, wherein ˜OH is alpha.
 10. 6α-Hydroxy-PGE₁, amide, a prostacyclin analog according to claim
 9. 11. 6α-Hydroxy-15-methyl-PGE₁, amide, a prostacyclin analog according to claim
 9. 12. 6α-Hydroxy-16,16-dimethyl-PGE₁, amide, a prostacyclin analog according to claim
 9. 13. 6α-Hydroxy-16,16-difluoro-PGE₁, amide, a prostacyclin analog according to claim
 9. 14. A prostacyclin analog according to claim 6, wherein ˜OH is a mixture of α-OH and β-OH.
 15. A prostacyclin analog according to claim 14, wherein Y₁ is cis--CH═CH--.
 16. 6-Hydroxy-cis-13-PGE₁, amide, a prostacyclin analog according to claim
 15. 17. A prostacyclin analog according to claim 14, wherein Y₁ is --C.tbd.C--.
 18. 6-Hydroxy-13,14-dide-ydro-PGE₁, amide, a prostacyclin analog according to claim
 17. 19. A prostacyclin analog according to claim 14, wherein Y₁ is trans--CH═C(Hal)--.
 20. 6-Hydroxy-14-chloro-PGE₁, amide, a prostacyclin analog according to claim
 19. 21. A prostacyclin analog according to claim 14, wherein Y₁ is --CH₂ CH₂ --.
 22. 6-Hydroxy-13,14-dihydro-PGE₁, amide, a prostacyclin analog according to claim
 21. 23. A prostacyclin analog according to claim 14, wherein Y₁ is trans--CH═CH--.
 24. A prostacyclin analog according to claim 23, wherein Z₁ is --(CH₂)_(g) --CH₂ --CF₂ --.
 25. 2,2-Difluoro-6-hydroxy-15-methyl-PGE₁, amide, a prostacyclin analog according to claim
 24. 26. A prostacyclin analog according to claim 23, wherein Z₁ is trans--(CH₂)_(g) --CH═CH--.
 27. trans-2,3-Didehydro-6-hydroxy-PGE₁, amide, a prostacyclin analog according to claim
 26. 28. A prostacyclin analog according to claim 23, wherein Z₁ is --(CH₂)_(g) --CH₂ --CH₂ --.
 29. A prostacyclin analog according to claim 28, wherein g is one.
 30. A prostacyclin analog according to claim 29, wherein ##STR8##
 31. 6-Hydroxy-17-phenyl-18,19,20-trinor-PGE₁, amide, a prostacyclin analog according to claim
 30. 32. A prostacyclin analog according to claim 29, wherein ##STR9##
 33. 6-Hydroxy-16-phenoxy-17,18,19,20-tetranor-PGE₁, amide, a prostacyclin analog according to claim
 32. 34. A prostacyclin analog according to claim 29, wherein R₇ is --(CH₂)_(m) --CH₃ --.
 35. A prostacyclin analog according to claim 34, wherein m is
 3. 36. A prostacyclin analog according to claim 35, wherein R₅ is methyl.
 37. 6-Hydroxy-15-methyl-PGE₁, amide, a prostacyclin analog according to claim
 36. 38. A prostacyclin analog according to claim 35, wherein R₅ is hydrogen.
 39. A prostacyclin analog according to claim 38, wherein at least one of R₃ and R₄ is fluoro.
 40. 6-Hydroxy-16,16-difluoro-PGE₁, amide, a prostacyclin analog according to claim
 39. 41. A prostacyclin analog according to claim 38, wherein at least one of R₃ and R₄ is methyl.
 42. 6-Hydroxy-16,16-dimethyl-PGE₁, amide, a prostacyclin analog according to claim
 41. 43. A prostacyclin analog according to claim 38, wherein R₃ and R₄ are both hydrogen.
 44. 6-Hydroxy-PGE₁, piperadyl amide, a prostacyclin analog according to claim
 43. 45. 6-Hydroxy-PGE₁, methylsulfonyl amide, a prostacyclin analog according to claim
 43. 46. 6-Hydroxy-PGE₁, pyridyl amide, a prostacyclin analog according to claim
 43. 47. 6-Hydroxy-PGE₁, amide, a prostacyclin analog according to claim
 43. 